Composition with sustained release of levodopa and carbidopa

ABSTRACT

The invention relates to a pharmaceutical composition comprising a therapeutically effective amount of levodopa and of carbidopa, dispersed in a hydrophilic matrix, said composition further comprising an organic acid. A subject of the invention is also a process for preparing the composition, comprising granulation, in particular in a fluidized bed, of the various components and compression of the granules obtained.

SUBJECT AND SUMMARY OF THE INVENTION

[0001] The present invention consists of a formulation with sustainedrelease of a combination of two active principles, namely levodopa andcarbidopa.

PRIOR ART

[0002] In the case of two combined active principles, it is desirable,for certain dosage forms, for them to have:

[0003] an extended release of the two active principles over a period ofseveral hours, and with identical release profiles for the twosubstances;

[0004] a stability of the formulation over time, for example over aperiod of at least 6 months under accelerated conditions as described inthe European and American pharmacopoeias.

[0005] This is particularly true for levodopa and carbidopacombinations. Specifically, carbidopa is a relatively fragile moleculeand formulations containing this product often show relatively poorconservation, particularly at high temperature and high humidity.

[0006] Various formulations corresponding to a levodopa/carbidopacombination with sustained release are disclosed in the literature.

[0007] Document U.S. Pat. No. 5,840,756 discloses a matrix based onhydroxypropylmethylcellulose, hydroxypropylcellulose an a carboxyvinylpolymer and containing different proportions of levodopa and carbidopa.This formulation is obtained by direct compression of the mixture of theconstituents. The drawback of such a process lies in the difficulty inobtaining a uniform distribution of the active principles during directcompression. This formulation does not have good stability.

[0008] Document EP-A-0 253 490 discloses a formulation of levodopa andcarbidopa uniformly dispersed in a polymeric matrix consisting of amixture of two polymers, one of which is water-soluble, such ashydroxypropyl(methyl)cellulose, and the other of which is weaklysoluble, such as polyvinyl acetate/crotonic acid copolymer. Such aformulation is, firstly, complex (it requires the steps of mixing theactive compounds with an aqueous-alcoholic solution of the polymers,drying, grinding, mixing with the lubricant and finally compressing intotablets), and secondly there is no indication as to the stability of thepreparation.

[0009] No formulation of the prior art makes it possible simultaneouslyto obtain a parallel sustained release of the two principles with highstability over time, while at the same time being simple in itscomposition and implementation.

SUMMARY OF THE INVENTION

[0010] The invention relates to a pharmaceutical composition comprisinga therapeutically effective amount of levodopa and of carbidopa,dispersed in a hydrophilic matrix, said composition further comprisingan organic acid.

[0011] According to one embodiment, the organic acid is chosen fromfumaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid,malonic acid and oxalic acid.

[0012] According to one embodiment, the organic acid represents from0.2% to 5% by weight relative to the weight of the composition.

[0013] According to one embodiment, the hydrophilic matrix representsfrom 10% to 80% by weight relative to the weight of the composition.

[0014] According to one embodiment, the hydrophilic matrix compriseshydroxypropylmethylcellulose.

[0015] According to one embodiment, the hydrophilic matrix comprises, asa percentage by weight relative to the weight of the composition,between 5% and 40% of hydroxypropylmethylcellulose with a viscosity ofabout 50 cP and between 5% and 40% by weight ofhydroxypropylmethylcellulose with a viscosity of about 3 cP.

[0016] According to one embodiment, the hydrophilic matrix moreovercomprises an insoluble substance.

[0017] According to one embodiment, the insoluble substance ismicrocrystalline cellulose.

[0018] According to one embodiment, the levodopa is present in an amountof between 50 mg and 300 mg.

[0019] According to one embodiment, the carbidopa is present in anamount of between 10 mg and 80 mg.

[0020] According to one embodiment, the composition is in the form ofgranules compressed together.

[0021] The composition according to the invention is useful in thetreatment of Parkinson's disease.

[0022] The invention also relates to a process for preparing acomposition according to the invention, comprising granulation of thevarious components and compression of the granules obtained.

[0023] According to one embodiment, the granulation is carried out in afluidized bed.

BRIEF DESCRIPTION OF THE FIGURES

[0024]FIG. 1 represents the dissolution as a function of time of thecomposition of Example 1.

DESCRIPTION OF THE INVENTION

[0025] The composition according to the invention comprises, in additionto the active principles, a hydrophilic matrix and an organic acid.

[0026] The Applicant has discovered, surprisingly, that the chemicalstability of carbidopa can be greatly improved by incorporating into theformulation a small amount of an organic acid. This organic acid istypically a weak organic acid such as fumaric acid. Many other weakorganic acids may be used to prevent the degradation of carbidopa, suchas, for example, citric acid, maleic acid, tartaric acid, ascorbic acidor glutamic acid.

[0027] The hydrophilic matrix generally comprises a gelling substancesuch as hydroxypropylmethylcellulose. Other gelling components may beused, such as polyvinylpyrrolidone, poly(vinyl alcohol),hydroxypropylcellulose, hydroxymethylcellulose or gelatin, alone or as amixture.

[0028] Mixtures of two different grades of hydroxypropylmethylcellulose,in particular of different viscosities (the viscosity is measured at 2%and at 20° C.), are suitable.

[0029] The hydrophilic matrix may also comprise a substance, in generalan insoluble substance such as microcrystalline cellulose. Otherinsoluble compounds may be used.

[0030] The amount of this insoluble substance present is generally in aninsoluble substance:gelling substance weight ratio of between 15:100 and50:100 and preferably 1:3.

[0031] Other conventional excipients may be used.

[0032] The invention is generally in the form of a tablet. This tabletis obtained in particular by compressing granules. These granules areadvantageously obtained by granulating the constituent principles, forexample according to a process in a fluidized air bed, followed bycompression.

[0033] This process of granulation in a fluidized bed is conventionaland known to those skilled in the art. According to the conventionalart, a powder or a mixture of powders (active principles+excipients) isplaced in suspension in the form of a fluidized bed in a granulator, anda solution containing a binder and, optionally, a surfactant is sprayedonto this bed to form granules. This technique of granulation in afluidized bed is disclosed in particular in, for example, “DieTablette”, by Ritschel, Ed. Cantor Aulendorf, pages 211-212.

[0034] The granulate obtained is then mixed with a lubricant present ina proportion generally of between 0.1% and 5% by weight, such as, forexample, magnesium stearate, sodium stearylfumarate, glyceryl behenateor any other lubricant known to those skilled in the art and disclosed,for example, in Banker G S, Rhodes C T: Modern Pharmaceutics (1996) ISBN0-8247-9371-4. In order to improve the flow of the mixture on the press,a flow regulator may also be added to the formulation, in a proportiongenerally of between 0.1% and 4% by weight. Such a substance may be, forexample, talc, modified or unmodified starch, or, preferably, colloidalsilica such as Aerosil® 200 manufactured by Degussa.

[0035] The conventional techniques of direct compression used in theprior art may also be used, although these are less preferred.

[0036] The tablets thus obtained are useful for treating Parkinson'sdisease. They also offer the advantage of avoiding the phenomena of“wearing-off and on-off” conventionally associated with standardformulations of levodopa and carbidopa, such as Sinemet® std.

[0037] The term “about” as used in the application means±10% of thevalue.

[0038] The examples which follow illustrate the invention withoutlimiting it.

EXAMPLES Example 1.

[0039] Granules are prepared from the following composition: Levodopa200.0 mg  Carbidopa (hydrate) 53.5 mg Hydroxypropylmethylcellulose 50 cP60.0 mg Hydroxypropylmethylcellulose 3 cP 90.0 mg Microcrystallinecellulose 50.0 mg Polyvinylpyrrolidone K30 15.0 mg Fumaric acid  2.0 mg

[0040] The levodopa, the carbidopa, the microcrystalline cellulose andthe two grades of hydroxypropylmethylcellulose are mixed together andplaced in a fluidized air bed (GPCG1, Glatt®). A solution ofpolyvinylpyrrolidone in water is prepared and the fumaric acid issuspended in this solution. To do this, it is convenient to use afumaric acid of micronized grade. The resulting suspension is sprayedonto the powder mixture at a pumping rate of 15 g/min, an inlet airtemperature of about 55° C. and a fluidized-air flow rate of 70 m³/h. Agranulate is thus obtained.

[0041] The granulate obtained is mixed with 1% by weight of sodiumstearylfumarate and 0.5% by weight of colloidal silica (Aerosil 200).The mixture is compressed on a Fette P2100 rotary press equipped withpunches with a diameter of 11 mm and a radius of curvature of 11 mm, toa mass of 415 mg and a hardness of 90 N. A rigorously identicalformulation, but without fumaric acid, is then prepared and compressedto a mass of 413 mg.

[0042] Study of the Degradation of Carbidopa

[0043] Action of Temperature on the Formulation

[0044] A tablet of each of the formulations is placed in a graduatedflask containing 50 ml of purified water and the mixture is stirreduntil the active principles have completely dissolved, and placed in anoven at 50° C. for 72 hours. The carbidopa concentration in each of thetwo solutions is determined by high performance liquid chromatographyaccording to the following method:

[0045] Operating conditions:

[0046] Mobile phase: 5% ethanol

[0047] 95% monobasic sodium phosphate monohydrate (5.2 g/l)

[0048] pH adjusted to 2.7 with orthophosphoric acid

[0049] Column: NUCLEOSIL C18 5 μ250×4.6 mm

[0050] Detection: 280 nm

[0051] Flow rate: 1.2 ml/min

[0052] Volume injected: 20 μA

[0053] Retention time: Levodopa: 3.2 min

[0054] Fumaric acid: 3.9 min

[0055] Carbidopa: 5.5 min

[0056] Diluent: 20% 1M H₃PO₄ and 80% mobile phase

[0057] Preparation of the Standard Solution:

[0058] Introduce accurately weighed amounts of about 200 mg of referencelevodopa and 53.5 mg of reference carbidopa into a 100 ml graduatedflask. Dissolve with 20 ml of H₃PO₄ in an ultrasonic bath for 5 minutes.Cool the solution to room temperature and make up to the graduation markwith the mobile phase. Take 10 ml of the solution and make up to 25 mlwith the mobile phase. Filter a few ml of the suspension through afilter (0.45μm).

[0059] The concentrations thus obtained are about:

[0060] Levodopa: 0.8 mg/ml

[0061] Carbidopa: 0.214 mg/ml

[0062] Preparation of the Sample Solution:

[0063] Introduce an accurately weighed amount of powder obtained fromground tablets corresponding theoretically to about 200 mg of levodopaand to about 53.5 mg of carbidopa into a 100 ml graduated flask.Dissolve with 20 ml of H₃PO₄ in an ultrasonic bath for 10 minutes. Coolthe solution to room temperature and make up to the graduation mark withthe mobile phase (if necessary, wet the neck of the flask with ethanolto eliminate the foam). Take 10 ml of the solution and make up to 25 mlwith the mobile phase. Filter a few ml of the suspension through afilter (0.45 μm).

[0064] Calculating the Results:

[0065] The amount Q1, expressed as % of levodopa, is given by thefollowing formula:

Q1=(Asam/Aref)×(Wref/Wsam)×(Vd sam/Vd ref)×(Wth/C)×100

[0066] where Asam=Area of the peak for the sample solution

[0067] Aref=Area of the peak for the reference solution

[0068] Wref=Weight of the reference levodopa

[0069] Wsam=Weight of the sample

[0070] Vd sam=Dilution factor for the sample

[0071] Vd ref=Dilution factor for the reference

[0072] Wth=Theoretical weight of the tablet

[0073] C=Levodopa content of the tablet

[0074] The amount Qc, expressed as % of carbidopa, is given by thefollowing formula:

Qc=(Asam/Aref)×(Wref/Wsam)×(Vd sam/Vd ref)×(Wth/C)×100

[0075] where Asam=Area of the peak for the sample solution

[0076] Aref=Area of the peak for the reference solution

[0077] Wref=Weight of the reference carbidopa

[0078] Wsam=Weight of the sample

[0079] Vd sam=Dilution factor for the sample

[0080] Vd ref=Dilution factor for the reference

[0081] Wth=Theoretical weight of the tablet

[0082] C=Carbidopa content of the tablet

[0083] Results Formulation with Control fumaric acid formulationCarbidopa (% of the initial value) 69.2 29.5

[0084] A very marked protective effect of fumaric acid on thedegradation of carbidopa is noted.

[0085] Action of Light on the Formulation

[0086] A tablet of each of the formulations is placed in a graduatedflask containing 50 ml of purified water and the mixture is stirreduntil the active principles have completely dissolved, and exposed tothe ambient laboratory light for 72 hours. The carbidopa concentrationin each of the two solutions is determined by high performance liquidchromatography according to the following method:

[0087] Results Formulation with Control fumaric acid formulationCarbidopa (% of the initial value) 96.7 66.8

[0088] The light-stability of carbidopa is also considerably improved bythe invention.

[0089] The release of active principle by the above formulation isstudied according to the method described in the edition of the USpharmacopoeia in force and with the following parameters:

[0090] Dissolution medium: 0.1M pH 2.0 citrate buffer

[0091] Volume: 1000 ml

[0092] Wavelength: 280 nm

[0093] Dissolution tool: 40 mesh basket

[0094] Stirring speed: 100 rpm

[0095] HPLC assay to separate the active principles

[0096] The dissolution curve is given in FIG. 1.

[0097] The dissolution profile obtained shows a sustained release of theactive principle over about 5 hours.

Example 2.

[0098] The above example is repeated, but replacing the fumaric acidwith ascorbic acid (these acids are used in the same amounts). Theformulation used is as follows: Levodopa 200.0 mg  Carbidopa (hydrate)53.5 mg Hydroxypropylmethylcellulose 50 cP 80.0 mgHydroxypropylmethylcellulose 3 cP 70.0 mg Microcrystalline cellulose50.0 mg Polyvinylpyrrolidone K30 15.0 mg Ascorbic acid  2.0 mg

[0099] The stability of the carbidopa in the above two formulations isstudied according to the protocol described previously, with exposure toheat or to light.

[0100] Results Action of heat (50° C. for 72 hours) Formulation withControl ascorbic acid formulation Carbidopa (% of the initial value)58.6 29.5

[0101] Action of light (ambient laboratory light for 72 hours)Formulation with Control ascorbic acid formulation Carbidopa (% of theinitial value) 94.3 66.8

[0102] The stability is still improved with ascorbic acid (although in aslightly lower proportion relative to the formulation containing fumaricacid).

[0103] The release of the active principles shows a profile similar tothat of the preceding formulation (although slightly slower, possibly onaccount of the presence of a larger amount of microcrystallinecellulose).

Example 3.

[0104] A tablet having the following composition is prepared: Levodopa200.00 mg  Carbidopa (hydrate) 53.50 mg Hydroxypropylmethylcellulose 50cP 50.00 mg Hydroxypropylmethylcellulose 3 cP 50.00 mg Colloidal silicondioxide  2.40 mg  Fumaric acid 10.00 mg FD & C yellow 10  0.03 mg FD & Cred 3  0.03 mg Sodium stearyl fumarate  7.30 mg

[0105] A 300 mg water solution is prepared by dissolving thehydroxypropylmethylcellulose 3 cP grade. The dyes are dissolved in 100mg of water and the micronised fumaric acid is suspended in thesolution. These two solutions are then mixed together. The levodopa, thecarbidopa, the colloidal silicon dioxide and thehydroxypropylmethylcellulose 50 cP grade are mixed together and placedin a fluidized air bed (GPCG1, Glatt®). The previously prepared solutionis sprayed onto the powder mixture at a pumping rate of 15 g/min, aninlet air temperature of about 55° C. and a fluidized-air flow rate of70 m³/h. A granulate is thus obtained.

[0106] The granulate obtained is mixed with the sodium stearylfumarate.The mixture is compressed on a Fette P2100 rotary press as previouslydisclosed.

[0107] Example 4.

[0108] Example 3 is repeated, but with the following composition:Levodopa 200.00 mg  Carbidopa (hydrate) 53.50 mgHydroxypropylmethylcellulose 50 cP 35.00 mg Hydroxypropylmethylcellulose3 cP 50.00 mg Colloidal silicon dioxide  2.40 mg Fumaric acid 10.00 mgFD & C yellow 10  0.03 mg FD & C red 3  0.03 mg Sodium stearyl fumarate 7.00 mg

[0109] Both example 3 and example 4 compositions exhibit improvedstability and sustained release.

1. Pharmaceutical composition comprising a therapeutically effectiveamount of levodopa and of carbidopa, dispersed in a hydrophilic matrix,said composition further comprising an organic acid.
 2. Compositionaccording to claim 1, in which the organic acid is chosen from fumaricacid, citric acid, ascorbic acid, maleic acid, glutamic acid, malonicacid and oxalic acid.
 3. Composition according to claim 1, in which theorganic acid represents from 0.2% to 5% by weight relative to the weightof the composition.
 4. Composition according to claim 1, in which thehydrophilic matrix represents from 10% to 80% by weight relative to theweight of the composition.
 5. Composition according to claim 1, in whichthe hydrophilic matrix comprises hydroxypropylmethylcellulose. 6.Composition according to claim 5, in which the hydrophilic matrixcomprises, as a percentage by weight relative to the weight of thecomposition, between 5% and 40% of hydroxypropylmethylcellulose with aviscosity of about 50 cP and between 5% and 40% by weight ofhydroxypropylmethylcellulose with a viscosity of about 3 cP. 7.Composition according to claim 1, in which the hydrophilic matrixmoreover comprises an insoluble substance.
 8. Composition according toclaim 7, in which the insoluble substance is microcrystalline cellulose.9. Composition according to claim 1, in which the levodopa is present inan amount of between 50 mg and 300 mg.
 10. Composition according toclaim 1, in which the carbidopa is present in an amount of between 10 mgand 80 mg.
 11. Pharmaceutical composition comprising a therapeuticallyeffective amount of levodopa and of carbidopa, dispersed in ahydrophilic matrix, said composition further comprising an organic acid,where this acid is chosen from fumaric acid, citric acid, ascorbic acid,maleic acid, glutamic acid, malonic acid and oxalic acid and representsfrom 0.2% to 5% by weight relative to the weight of the composition. 12.Composition according to claim 11, in which the hydrophilic matrixrepresents from 10% to 80% by weight relative to the weight of thecomposition.
 13. Composition according to claim 11, in which thehydrophilic matrix comprises hydroxypropylmethylcellulose. 14.Composition according to claim 13, in which the hydrophilic matrixcomprises, as a percentage by weight relative to the weight of thecomposition, between 5% and 40% of hydroxypropylmethylcellulose with aviscosity of about 50 cP and between 5% and 40% by weight ofhydroxypropylmethylcellulose with a viscosity of about 3 cP. 15.Composition according to claim 11, in which the hydrophilic matrixmoreover comprises an insoluble substance.
 16. Composition according toclaim 15, in which the insoluble substance is microcrystallinecellulose.
 17. Composition according to claim 11, in which the levodopais present in an amount of between 50 mg and 300 mg.
 18. Compositionaccording to claim 11, in which the carbidopa is present in an amount ofbetween 10 mg and 80 mg.
 19. Pharmaceutical composition comprising atherapeutically effective amount of levodopa and of carbidopa, dispersedin a hydrophilic matrix, said composition further comprising an organicacid, where this acid is chosen from fumaric acid, citric acid, ascorbicacid, maleic acid, glutamic acid, malonic acid and oxalic acid andrepresents from 0.2% to 5% by weight relative to the weight of thecomposition, and where the hydrophilic matrix represents from 10% to 80%by weight relative to the weight of the composition, said hydrophilicmatrix comprising as a percentage by weight relative to the weight ofthe composition, between 5% and 40% of hydroxypropylmethylcellulose witha viscosity of about 50 cP and between 5% and 40% by weight ofhydroxypropylmethylcellulose with a viscosity of about 3 cP. 20.Composition according to claim 19, in which the levodopa is present inan amount of between 50 mg and 300 mg and the carbidopa is present in anamount of between 10 mg and 80 mg.
 21. Composition according to claim 1,in the form of granules compressed together.
 22. Composition accordingto claim 11, in the form of granules compressed together. 23.Composition according to claim 19, in the form of granules compressedtogether.
 24. Composition according to claim 1, for its use in thetreatment of Parkinson's disease.
 25. Composition according to claim 11,for its use in the treatment of Parkinson's disease.
 26. Compositionaccording to claim 19, for its use in the treatment of Parkinson'sdisease.
 27. Process for preparing a pharmaceutical compositioncomprising a therapeutically effective amount of levodopa and ofcarbidopa, dispersed in a hydrophilic matrix, said composition furthercomprising an organic acid, comprising: (a) mixing a therapeuticallyeffective amount of levodopa and of carbidopa with a hydrophilic matrix;(b) granulation of the various components of step (a); and (c)compression of the granules obtained from step (b).
 28. Processaccording to claim 27, in which the granulation is carried out in afluidized bed.
 29. Process for preparing a pharmaceutical compositioncomprising a therapeutically effective amount of levodopa and ofcarbidopa, dispersed in a hydrophilic matrix, said composition furthercomprising an organic acid, where this acid is chosen from fumaric acid,citric acid, ascorbic acid, maleic acid, glutamic acid, malonic acid andoxalic acid and represents from 0.2% to 5% by weight relative to theweight of the composition, comprising: (a) mixing a therapeuticallyeffective amount of levodopa and of carbidopa with a hydrophilic matrix;(b) granulation of the various components of step (a); and (c)compression of the granules obtained from step (b).
 30. Processaccording to claim 29, in which the granulation is carried out in afluidized bed.
 31. Process for preparing a pharmaceutical compositioncomprising a therapeutically effective amount of levodopa and ofcarbidopa, dispersed in a hydrophilic matrix, said composition furthercomprising an organic acid, where this acid is chosen from fumaric acid,citric acid, ascorbic acid, maleic acid, glutamic acid, malonic acid andoxalic acid and represents from 0.2% to 5% by weight relative to theweight of the composition, and where the hydrophilic matrix representsfrom 10% to 80% by weight relative to the weight of the composition,said hydrophilic matrix comprising as a percentage by weight relative tothe weight of the composition, between 5% and 40% ofhydroxypropylmethylcellulose with a viscosity of about 50 cP and between5% and 40% by weight of hydroxypropylmethylcellulose with a viscosity ofabout 3 cP, comprising: (a) mixing a therapeutically effective amount oflevodopa and of carbidopa with a hydrophilic matrix; (b) granulation ofthe various components of step (a); and (c) compression of the granulesobtained from step (b).
 32. Process according to claim 31, in which thegranulation is carried out in a fluidized bed.